Localization of glial cell line-derived neurotrophic factor receptor alpha and c-ret mRNA in rat central nervous system

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor that influences the survival and function of several neuronal populations in the central (CNS) and peripheral nervous systems. The actions of GDNF are mediated by a multicomponent receptor complex composed of the tyrosine kinase product of c-ret and the ligand-binding protein GDNF receptor alpha (GDNFR-alpha). In the present study, we used in situ hybridization to localize cells expressing the mRNA for these GDNF receptor subunits in rat CNS. As reported previously, GDNFR-alpha and c-ret mRNA are present in the substantia nigra and ventral tegmental area, regions containing GDNF-responsive dopamine neurons. However, both mRNA were found in motor neurons of spinal cord and brainstem nuclei that innervate skeletal muscle. These areas include alpha motor neurons in the ventral horn of spinal cord and neurons in hypoglossal, facial, trigeminal, and abducens nuclei. In areas rostral to the substantia nigra, c-ret mRNA is not detected, whereas GDNFR-alpha is found in numerous brain structures, including the hippocampus, cortex, medial geniculate, and the medial habenula, the latter area expressing the highest levels of GDNFR-alpha mRNA in brain. These results provide evidence that c-ret and GDNFR-alpha mRNA are expressed in neuronal populations involved in motor function and provides further support for GDNF as a target-derived neurotrophic for these motor neurons. The observation that GDNFR-alpha mRNA is localized in several brain structures that do not contain detectable levels of c-ret mRNA indicates that either GDNFR-alpha utilizes signal transduction molecules other than c-ret in these areas or that other GDNF-like ligands that utilize GDNFR-alpha as a receptor may be present.

mGluR2/3 agonist LY379268, by enhancing the production of GDNF, induces a time-related phosphorylation of RET receptor and intracellular signaling Erk1/2 in mouse striatum

“…The diverse biological actions of GDNF are mediated through its RET receptor tyrosine kinase (Trupp et al, 1996;Yu et al, 1998;Paratcha et al, 2001) and RET protein has been found expressed in the mesencephalic dopaminergic neurons and their striatal terminals, but not in the intrastriatal neurons (Trupp et al, 1997;Golden et al, 1998;Tsuzuki et al, 1995;Glazner et al, 1998;Walker et al, 1998;Honda et al, 1999;He et al, 2008). However, in our hand, it was possible to detect RET protein in the striatum but not in the substantia nigra.…”

“…Here we examined the effects of LY379268 treatment on activation levels of RET Tyr1062 in both substantia nigra and striatum, since RET protein has been found in the mesencephalic dopaminergic neurons and their striatal terminals (Tsuzuki et al, 1995;Glazner et al, 1998;Walker et al, 1998;Honda et al, 1999).…”

Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat

“…The GDNF receptor complex consists of two components, GFR␣-1 and the Ret receptor, both of which are expressed by nigral DA neurons. [62][63][64] While the expression of GFR␣-1 and Ret have not been examined in the aged rat brain, age-related alterations in the distribution or expression of the GDNF receptor complex may reduce the protective effects of GDNF in the lesioned SN.…”

Retrograde Signaling onto Ret during Motor Nerve Terminal Maturation

“…Ret (Fig. 2 E) and GFR␣1 (Glazner et al, 1998;Mikaels et al, 2000) are abundantly expressed in most neurons of both these nuclei, and Ret-deficient mice no longer express any active Ret receptors, so the differences in dependency does not reflect distinct expression and/or localization of the receptor as a consequence of the lesion. GDNF expressed in Schwann cells is rapidly upregulated after sciatic nerve lesion with peak levels at 7 d and soluble GFR␣1 released from these cells may act on regenerating motor axons (Naveilhan et al, 1997;Fundin et al, 1999;Paratcha et al, 2001).…”